SAR-20347

SAR-20347 is an inhibitor of TYK2, JAK1, JAK2 and JAK3 with IC₅₀s of 0.6, 23, 26 and 41 nM, respectively. IC50 & Target:IC50: 0.6 nM (TYK2), 23 nM (JAK1), 26 nM (JAK2), 41 nM (JAK3)^[1] In Vitro: When NK-92 cells are stimulated with IL-12, SAR-20347 potently inhibits IL-12-mediated STAT4 phosphorylation, a TYK2-dependent event, with an IC₅₀ of 126 nM. SAR-20347 demonstrates a selectivity of TYK2>JAK1>JAK2>JAK3. Cells without IL-12 in the culture media have no measureable IFN-γ, while cells incubated with IL-12 and SAR-20347 demonstrate dose-dependent inhibition of IFN-γ production. SAR-20347 dose-dependently inhibits the production of secreted embryonic alkaline phosphatase (SEAP) with greatest inhibition occurring with 5 μM of SAR-20347 in these experiments^[1]. In Vivo: 60 mg/kg SAR-20347 inhibits the production of IFN-γ in the serum by 91% compare to vehicle-treated animals, demonstrating that SAR-20347 can inhibit TYK2 signaling in vivo. SAR-20347 treatment significantly reduces IL-17 production as measured by average signal intensity, consistent with the gene expression analysis^[1].